This research proposal will investigate the metabolism and toxicity of cadmium in mammalian systems. The role of metallothionein in metal metabolism and toxicity will also be evaluated. Three types of mammalian systems will be utilized: Populations environmentally or occupationally exposed to cadmium, rats and mice experimentally exposed to the metal, and primary cultures of adult rat hepatocytes and renal tubular epithelial cells pulsed with the metal. The studies in humans will evaluate whether urinary metallothionein is related to the tissue cadmium levels and whether its concentrations in urine is also related to the renal function. Metallothionein levels in human and animal tissues, cells, and biological fluids will be determined using the radio-immunoassay developed in this laboratory. Improvements in the assay will be made to further increase its sensitivity. Studies in rats will be carried out to understand the role of metallothionein in metal-induced renal dysfunction. Mice will be used to address the issue of strain differences in susceptibility to testicular and hepatic damage induced by acute cadmium exposure. The cell culture studies are planned to gain insight about the mechanism of metal uptake, metallothionein induction and its toxicity. There is a need to identify a specific biological indicator of cadmium exposure since blood and urinary cadmium levels are only indicative of recent exposure. It is expected that as a result of the studies proposed in this application the assay of metallothionein in biological fluids may evolve as the much needed routine screening procedure for assessing the extent of exposure and hence toxicity of the metal in human populations that may be at risk.